Abstract P4-14-02: Molecular response in breast cancer tumors treated with neoadjuvant chemotherapy with and without bevacizumab: Results from NeoAva - A randomized phase II study
Authors: O Engebraaten, C Vaske, M Krohn, L Silwal-Pandit, HK Moen Vollan, EK Møller, S Nord, T Fleischer, E Borgen, H Edvardsen, Ø Garred, A Fangberget, MM Holmen, E Schlichting, H Skjerven, S Lundgren, E Wist, B Naume, A-L Børresen-Dale, VN Kristensen
Journal: Cancer Research (2013)

Abstract Patients treated with bevacizumab in addition to regular neoadjuvant chemotherapy achieve an increased rate of pathological complete response (pCR). The molecular characteristics of responding and non-responding tumors, including how treatment combinations influence the gene expression profiles and the signaling pathways, may be useful predictors of antiangiogenic response. The NeoAva study included patients with HER2 negative primary tumors of ≥25 mm that were randomized (1:1) to receive neoadjuvant chemotherapy (4 x FEC100 + 12 weeks of taxane-based therapy) with or without bevacizumab. Mammography, ultrasound and MR imaging were used for response evaluation, in addition to final pathology assessment. In the first part of the study 74 patients were evaluable for tumor response. The tumor size at time of inclusion was T2, T3 and T4 in 24.3%, 67.6% and 8.1% of the patients, respectively. Lymph node metastases were detected in 56.7% of the patients at inclusion and 82.4% were hormone receptor positive. There were no significant differences in the tumor size, lymph node or hormone receptor status between the treatment arms. The patients were randomized with bevacizumab + chemotherapy (n = 37) and treatment with chemotherapy alone (n = 37). Of the nine patients who achieved pCR in breast and axilla (12.2%), seven patients received bevacizumab (7/37), while two were treated with chemotherapy alone (2/37). Four of the patients with pCR were hormone receptor negative, of which three received bevacizumab. Of the remaining five hormone receptor positive tumors that achieved complete response, four received bevacizumab. In the second part of the study we evaluated gene expression signatures by RNA microarray and the time-response of pathways to treatment, using pathway analysis that integrates copy number and gene expression (Paradigm). Biopsies for molecular analyses were collected before therapy, after 12 weeks, and at surgery. Treatment associated gene expression changes to chemotherapy were subtracted, and bevacizumab associated differential expression was observed for 1069 genes. Furthermore, molecular profiling of the tumor tissue was performed at DNA level by copy number analysis (Affymetrix, SNP6.0) and mRNA level by gene expression arrays(Agilent 60K). At the screening time point, we found high proliferation through the activity of cyclin E and B and the transcription factors E2F1 and FOXM1. At 12 weeks, there was a strong increase in predicted p53 signaling, due to increased activity of downstream target genes. The 12 week timepoint was also characterized by an increase of Calmodulin 1, MAPK3, as well as Peroxisome proliferator-activated receptor alpha (PPAR-alpha), and both trends continued to the 25 week time point. At 25 weeks, there were broad increases in ERK1/2, JUN, and FOS signaling. The 25 week timepoint also showed a T-cell response signature that from increased activity of GATA3, IL6/IL6R, IL4, and NFATC1 and NFATC2. These results suggest that there are measurable and strongly significant aberrations in molecular activity during treatment, which may be useful to monitor treatment response. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-14-02.